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  • Review Article
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Role of ampa receptor endocytosis in synaptic plasticity

Nature Reviews Neuroscience volume 2, pages 315–324 (2001)Cite this article

Key Points

  • The activity of several signalling receptor families is modulated by their endocytosis from the cell surface. Internalization of receptors can not only attenuate further response of receptors to extracellular signals, but also relocalize the receptors into functional intracellular signalling complexes. Despite significant differences in structure and function between receptor families, there are steps in the process of receptor endocytosis that are often conserved. Receptor phosphorylation, association with adaptor proteins and internalization via clathrin-coated pits regulates the surface expression of many receptor types following agonist stimulation.

  • Studies over the past five years or so have suggested that AMPA-type glutamate receptors (AMPARs) are regulated by their physical transport in and out of the synaptic membrane. Throughout development, synapses are observed that do not express detectable levels of AMPARs. Such synapses can be detected electrophysiologically, and during long-term potentiation (LTP) can be modified such that functional AMPARs rapidly appear, suggesting the possibility of regulated receptor insertion. Activity-dependent long-term depression (LTD), however, is associated with a rapid loss of surface, synaptic AMPARs indicating possible internalization.

  • Recent immunocytochemical and biochemical studies have provided direct evidence that AMPARs are, in fact, internalized in response to several extracellular stimuli. Similar to other receptor types, endocytosis of AMPARs is through clathrin-coated pits and involves an association of the receptor with a clathrin-adaptor protein. Disruption of AMPAR endocytosis blocks the expression of common forms of LTD, indicating that internalization of the receptors is involved in these forms of plasticity.

  • Several identified signalling pathways drive the endocytosis of AMPARs. Activation of insulin, NMDA, metabotropic glutamate and AMPA receptors can all stimulate the endocytosis of AMPARs. Cytosolic calcium elevations and calcineurin activation are necessary for AMPAR endocytosis triggered by several of the signalling pathways. The interactions of the GluR2 AMPAR subunit with the cytosolic proteins PICK1 and GRIP/ABP are regulated by phosphorylation of the receptor and have been implicated in the regulation of AMPAR endocytosis.

  • The level of surface expression of AMPARs is apparently regulated by a balance of the insertion and removal of receptors. In addition to regulated endocytosis, AMPARs are also subject to active delivery to the synapse following CaMKII activation. These two phenomenon provide mechanisms by which synaptic strength can be rapidly modulated. AMPARs also constitutively cycle at the synaptic surface with equal rates of exocytosis and endocytosis, providing a means to maintain synaptic receptor expression levels.

  • Studies of the regulation of AMPAR endocytosis have helped in the development of detailed models for the expression of LTD at hippocampal and cerebellar synapses. LTD involves the coordinated modulation of regulatory proteins that interact with AMPARs and are potentially involved in receptor stabilization, as well as the modification of the endocytic machinery itself. This causes rapid internalization of AMPARs, thereby reducing overall synaptic strength.

Abstract

Activity-mediated changes in the strength of synaptic communication are important for the establishment of proper neuronal connections during development and for the experience-dependent modification of neural circuitry that is believed to underlie all forms of behavioural plasticity. Owing to the wide-ranging significance of synaptic plasticity, considerable efforts have been made to identify the mechanisms by which synaptic changes are triggered and expressed. New evidence indicates that one important expression mechanism of several long-lasting forms of synaptic plasticity might involve the physical transport of AMPA-type glutamate receptors in and out of the synaptic membrane. Here, we focus on the rapidly accumulating evidence that AMPA receptors undergo regulated endocytosis, which is important for long-term depression.

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Figure 1: Endocytosis of cell-surface signalling receptors.
Figure 2: Activation of several membrane receptors can trigger AMPAR endocytosis.
Figure 3: Electron micrographs of coated vesicles in dendritic spines.
Figure 4: Model of regulated AMPAR endocytosis during long-term depression in two systems.
Figure 5: Model of AMPAR cycling and insertion.

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Authors and Affiliations

  1. Department of Neuroscience, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Reed C. Carroll

  2. Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, 94143, California, USA

    Eric C. Beattie & Mark von Zastrow

  3. Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University School of Medicine, Palo Alto, 94304, California, USA

    Eric C. Beattie & Robert C. Malenka

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  1. Reed C. Carroll
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DATABASE LINKS

AMPARs

insulin receptor

EGFR

TrkA

AP2

GABAARs

NMDARs

dynamin

amphiphysin

PP2B

PP1

PKC

GluR2

NSF

GRIP1

PICK

SNAP

GluR1

CaMKII

GluR4

calpain

PKA

ENCYCLOPEDIA OF LIFE SCIENCES

AMPA receptors

Glossary

CLATHRIN

A major structural component of coated vesicles that are implicated in protein transport. Clathrin heavy and light chains form a triskelion, the main building element of clathrin coats.

AP2

A heterotetrameric complex that serves as an adaptor, linking membrane receptors to clathrin-coated pit endocytic machinery.

BENZODIAZEPINES

Pharmacologically active molecules with sedative and anxiolytic effects. They act by binding to the GABA receptor γ subunit and potentiating the response elicited by the transmitter.

ENDOSOME

Organelle that carries materials ingested by the cell and passes them to lysosomes for degradation or recycles them to the cell surface.

SILENT SYNAPSE

A synapse that contains NMDA receptors but no AMPA receptors and therefore is functionally silent during low-frequency, basal synaptic transmission.

EPITOPE-TAGGED MOLECULE

A protein to which the immunological determinant of an antigen has been artificially added, allowing for its subsequent detection with the corresponding antibody.

QUANTAL SIZE

The response of the postsynaptic membrane to the transmitter contained in a single synaptic vesicle.

DOMINANT-NEGATIVE

A mutant protein that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

DYNAMIN

A small GTP-binding protein that is essential for clathrin-mediated endocytosis. It is believed to be involved in fission after invagination of endocytic vesicles.

SYNAPTONEUROSOME

The presynaptic terminal isolated in conjunction with the postsynaptic spine after subcellular fractionation. This structure retains the anatomical integrity of the synapse.

BAPTA-AM

A derivative of the Ca2+ chelator BAPTA with its four carboxylate groups masked by esterifying groups, making it membrane permeable. Upon cleavage by cellular esterases, BAPTA is unable to pass back out of the cell. BAPTA-AM allows buffering of intracellular Ca2+ changes.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. They can bind to the carboxyl termini of proteins, or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs-large, zona occludens-1).

POSTSYNAPTIC DENSITY

An electron-dense thickening underneath the postsynaptic membrane at excitatory synapses that contains receptors, structural proteins linked to the actin cytoskeleton and signalling machinery, such as protein kinases and phosphatases.

N-ETHYLMALEIMIDE-SENSITIVE FACTOR

An ATPase that is a key component of the membrane fusion machinery.

RECTIFICATION

The property whereby current through a channel does not flow with the same ease from the inside as from the outside. In inward rectification, for instance, current into the cell flows more easily than out of the cell through the same population of channels.

BREFELDIN A

A fungal metabolite that affects membrane transport and the structure of the Golgi apparatus.

TETANUS TOXIN

The causative agent of tetanus. Tetanus toxin blocks transmitter release as a result of synaptobrevin proteolysis.

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Carroll, R., Beattie, E., von Zastrow, M. et al. Role of ampa receptor endocytosis in synaptic plasticity. Nat Rev Neurosci 2, 315–324 (2001). https://doi.org/10.1038/35072500

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